Contamination Control Policy

Rationale:  An important element of the protection of patient safety, our highest priority, is preventing contamination and maintaining sterility, as applicable, for products or clinical materials. We have the important responsibility to assure controls are in place to prevent exposure to unintended and potentially harmful materials by patients being treated with products or participating in clinical trials.  Equally important is the protection of personnel working with materials from exposure levels that could exceed safe limits. 

Policy objective:  To define the expectations in implementing containment controls designed to minimize the likelihood of contamination and if applicable to assure the maintenance of sterility.

Procedures will be implemented to assure:

  • Establishment of effective means to contain ingredients, in process and finished materials to the manufacturing equipment and containers designed for their use, and which prevent airborne or physical transmittal of foreign materials into ingredients, in process, or finished products or product contact surfaces.
  • Application of risk based control mechanisms to establish steps to be taken to control cross contamination.  Factors to be considered include, but may not be limited to, toxic risk of materials; physical properties that present contamination risk; product contact surfaces; use of lubricants; establishment and monitoring of air pressure differential cascades in manufacturing areas; filtration of air, water, steam, gases, and vacuum; the proper use of cleaning materials, sanitizers, and application of pesticides; and the use of personal protective equipment for employees who work with high risk materials.
  • Classification of processing areas utilizing accepted international norms for viable and non-viable particulate levels
  • Design of facilities and utilities to ensure appropriate contamination controls and if applicable aseptic conditions
  • Definition of standards for and types of personal protective equipment (PPE) and procedures for donning PPE, plus additional personnel controls (such as hand washing and sanitization), and the exclusion of inappropriate materials (such as fiber shedding paper) as conditions of entry into classified areas.
  • Establishment of alert and action levels of viable and nonviable particulate matter in air, water, gases, product contact surfaces and personnel, together with monitoring methods and frequency, and steps to be taken when such levels are exceeded.
  • Assessment and validation of the effectiveness of containment controls, through methods such as periodic visualization of airflow patterns; water fills; media fills; and oversight of employee practices

Thoughts on ISPE 2022 Aseptic Conference

Just finished up the 2022 ISPE Aseptic Conference, and here are a few thoughts.

EU GMP Annex 1 expected in later half of the year

Paul Gustafson, chair of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) and a senior corporate regulatory compliance and enforcement advisor with Health Canada, stated that the plan was to issue the widely anticipated Annex 1 in mid-year 2022. He repeatedly said July to September so that is interesting news and start getting your contamination control strategies going. There will be a one-year period before in force, with 2 years on some of the lyophilizer requirements.

For those keeping track, it retains the provision calling for testing filters used in the sterilization process, pre-use, post-sterilization integrity testing (PUPSIT). The PUPSIT provision “has driven a substantial amount of discussion and has resulted in a number of papers being drafted,” said Gustafson. This was a very gracious understatement, and I have to admit I really admired his Canadian humor.

FDA continues to evaluate COVID inspection measures

Alonza Cruse, Director of the Office of Pharmaceutical Quality Operations at FDA/ORA did a thorough job going through the COVID measures of Remote Regulatory Assessments and Remote Interactive Evaluations and discussed how the agency was in the process of learning how best to do things going forward.

He also clearly state how they were continuing to get back to normal inspections and discussed new personnel in foreign offices, such as India.

Highlights from Panels

One of my favorite panels was Jo Ann Jacobs and Kara Vogt speaking on “Building Resiliency into Single-Use-Technology Systems” They laid out some good work they are doing as part of a startup to design good functional equivalency and supplier management, obviously learning from PPAP and similar measures. Quite well done. While it leans heavily into my own practice around functional equivalency it was good to see such a rock-solid implementation, and I felt like I learned a few good ideas.

I spoke on Contamination Control, Risk Management and the Quality Management System, having a blast doing so. I was followed by Christa Myers who spoke on “Contamination Control Strategy: From Annex 1 Draft Requirements to Implementation in Practice.” We made a good duo and between the two I hope participants got a real solid idea on how to do this contamination control strategy effectively.

I learned a lot about robotics and isolators.

Still a big fan of ISPE’s Women in Pharma.

Environmental Impact for Risk Assessments

Contamination occurs in two ways:

  • Environmental contamination results from the ingress of contaminants from the surrounding production areas or even from outside environments
  • Cross-contamination is defined as contamination of a starting material, intermediate product or finished product with another starting material or product during production.

Whether performing risk assessments or impact assessments there are six factors to consider in order to determine environmental impact and to inform contamination control.

  1. Amenability of equipment and surfaces to cleaning and sanitization
  2. Personnel presence and flow
  3. Material flow
  4. Proximity to open product or exposed direct product-contact material
  5. Interventions/operations by personnel and their complexity
  6. Frequency of interventions/process operations.

Risk Assessment for Environmental Monitoring

Maybe you’ve been there too, you need to take a risk-based approach to determine environmental monitoring, so you go to a HAACP or FMEA and realize those tools just do not work to provide information to determine how to distribute monitoring to best verify that processes are operating under control.

What you want to do is build a heat map showing the relative probability of contamination in a defined area or room| covering six areas:

  1. Amenability of equipment and surfaces to cleaning and sanitization
  2. Personnel presence and flow
  3. Material flow
  4. Proximity to open product or exposed direct product-contact material
  5. Interventions/operations by personnel and their complexity
  6. Frequency of interventions/process operations.

This approach builds off of the design activities and is part of a set of living risk assessments that inform the environmental monitoring part of your contamination control strategy.

Hope to see you in Bethesda to discuss more!

Regulatory Requirements for Contamination Control

A list of Regulatory documents that apply to contamination control.

  1. European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Chapter 3: Premises and Equipment, (2014)
  2. European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Chapter 5: Production, (2014)
  3. European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Part II: Basic Requirements for Active Substances used as Starting Materials, (2014)
  4. European Union, Guidelines of 19 March 2015 on the formalized risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use, Official Journal of the European Union, (2015/C 95/02), (2015)
  5. European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Annex 2: Manufacture of Biological active substances and Medicinal Products for Human Use, (2018)
  6. European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Annex 3 Manufacture of Radiopharmaceuticals, (2008)
  7. European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Annex 14 Manufacture of Medicinal Products Derived from Human Blood or Plasma, (2011)
  8. European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products, (2017)
  9. European Union, Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use, Official Journal of the European Union, (2013/C 343/01), (2013),
  10. European Union, Guidelines of 19 March 2015 on principles of Good Distribution Practice of active substances for medicinal products for human use, Official Journal of the European Union, (2015/C 95/01), (2015)
  11. EMA Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (20 November 2014)
  12. U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, subpart C = Building and Facilities, sec. 211.42 Design and construction features (b), (c)
  13. U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, Subpart F – Production and Process Controls, sec. 211.113 Control of microbial contamination (a), (b)
  14. U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, Subpart B – Organization and Personnel, sec.211.28 Personnel responsibilities (a)
  15. U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, Subpart E – Control of Components and Drug Product Containers and Closures, sec. 211.80 General requirements. (b)
  16. U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, Subpart E – Control of Components and Drug Product Containers and Closures, sec. 211.84 Testing and approval or rejection of components, drug product containers, and closures (d)
  17. U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, Subpart D – Equipment, sec. 211.67 Equipment cleaning and maintenance (a)
  18. U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, Subpart C – Buildings and Facilities, sec. 211.56 Sanitation (c)
  19. U.S. Food & Drug Administration, Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice, (2004)
  20. U.S. Food & Drug Administration, Guidance for Industry – Good Manufacturing Practice Considerations for Responding to COVID-19 Infection in Employees in Drug and Biological Products Manufacturing, (2020)
  21. U.S. Food & Drug Administration, Guidance for Industry – Guidance for Industry Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross Contamination, (2013)
  22. U.S. Food & Drug Administrationn, Guidance for Industry Current Good Manufacturing Practice—Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act, Draft Guidance. https://www.fda.gov/media/88905/download (accessed Mar 6, 2022)
  23. Pharmaceutical Inspection Co-operation Scheme gmp guide, 2nd targeted consultation document on revision of annex 1
  24. Pharmaceutical Inspection Co-operation Schemepharmaceutical inspection co-operation scheme gmp guide, ps inf 25 2019 (rev. 1) draft, manufacture of advanced therapy medicinal products for human use
  25. Pharmaceutical Inspection Co-operation Scheme gmp guide, ps inf 26 2019 (rev. 1) draft, manufacture of biological medicinal substances and products for human use
  26. Pharmaceutical Inspection Co-operation Scheme gmp guide, pe 009-15 (part i), guide to good manufacturing practice for medicinal products part i
  27. Pharmaceutical Inspection Co-operation Scheme gmp guide, pe 009-15 (part ii), guide to good manufacturing practice for medicinal products part ii
  28. Pharmaceutical Inspection Co-operation Scheme gmp guide, pe 009-15 (annexes), guide to good manufacturing practice for medicinal products annexes
  29. World Health Organisation, good manufacturing practices for pharmaceutical products: main principles, annex 2, who technical report series 986, 2014,
  30. World Health Organisation, who good manufacturing practices for active pharmaceutical ingredients (bulk drug substances), annex 2, who technical report series 957, 2010
  31. World Health Organisation, points to consider for manufacturers and inspectors: environmental aspects of manufacturing for the prevention of antimicrobial resistance annex 6, who technical report series 1025, 2020
  32. World Health Organisation, WHO good manufacturing practices for sterile pharmaceutical products, annex 6, who technical report series 961, 2011
  33. World Health Organisation, WHO good manufacturing practices for biological products, annex 3, who technical report series 996, 2016
  34. World Health Organisation, WHO good manufacturing practices for the manufacture of investigational pharmaceutical products for clinical trials in humans, annex 7, who technical report series 863, 1996
  35. World Health Organisation, WHO good manufacturing practices for radiopharmaceutical products annex 2, who technical report series 1025, 2020
  36. World Health Organisation, WHO GMP for Pharmaceutical Products containing Hazardous Substances, TRS 957, Annex-3 (2010)
  37. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use, Quality Risk Management, Q8 (R2), Pharmaceutical Development, August 2009. https://database.ich.org/sites/default/files/Q8%28R2%29%20Guideline.pdf (Accessed Mar 06, 2022)
  38. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use, Quality Risk Management Q9, November. https://database.ich.org/sites/default/files/Q9%20Guideline.pdf (accessed Mar 06, 2022).
  39. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use, pharmaceutical quality system Q10. https://database.ich.org/sites/default/files/Q10%20Guideline.pdf (accessed Mar 06, 2022).