CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING

1. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING A PRESENTATION BY PHARM R.A. BINITIE (ASSISTANT DIRECTOR) DRUG EVALUATION AND RESEARCH DIRECTORATE NAFDAC

2. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING OUTLINE • INTRODUCTION • BETA LACTAMS AND HEALTH CHALLENGES • REGULATORY CONCERNS FOR MANUFACTURING GMP • NEED FOR CONTAINMENT/RISKS OF CONTAINMENT FAILURES • CONTAINMENT CONTROLS • CONCLUSION

3. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING INTRODUCTION (i) • Beta(ß) Lactam antibiotics are a class of broad spectrum antibiotics, consisting of all antibiotics that contains a ß-lactam ring( part of core ) in their molecular structures. They are anti-infective agent that kill or inhibit an infectious microbe or agent and stops it from spreading. • ß -Lactam is of interest in pharmaceutical manufacturing because of potential health risk associated with it

4. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING INTRODUCTION (ii) • Penicillin and non penicillin beta lactam are sensitizing agent • Are possible sources or concern for cross contamination • Cross contamination can trigger drug induced hypersensitivity reaction in people • Beta lactam antibiotics are one of the largest group of antibiotics or antibacterial products used clinically to combat most resistant pathogen . • Cross contamination trigger needs for containment in beta lactam manufacturing

5. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING BETA –LACTAM ANTIBIOTICS Basically include: • Penicillins • ( eg methicillin, cloxacillin, dicloxacillin, ampicillin, amoxicillin, pivacillin, benzyl penicillin etc) • Cephalosporins(cephalexin, cefaclor) • Penems ( imipenem, meropenem) • Carbacephems ( loracarbef) • Monobactams (Aztreonam) • Beta-lactamase inhibitors

6. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING CHALLENGES OF BETA –LACTAMS • Suitable animal or receptor testing models exists to predict human sensitivity • Threshold for allergic response is extremely low and difficult to detect. • Hypersensitivity reaction may be serious and life threatening • Defining the minimal dose at which allergic response are unlikely to occur is difficult • Some Beta lactam intermediates compounds and derivates possesses sensitization and cross –reactivity properties

7. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING SOME DEFINITIONS • What is contamination ? The undesired introduction of a chemical or a microbiological nature or of a foreign matter into or onto a starting material or intermediate during production, sampling, repacking, storage and transport • What are contaminants? Are impurities from all sources that can affect the intermediate or product quality and lead to premature spoilage • What is cross contamination? Drug cross contamination is the contamination of one drug with one or more different drug product OR "Contamination of a starting material, intermediate product, or finished product with one or more another starting material or a product during production".

8. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING SOURCES OF CROSS CONTAMINATION Cross-contamination can result from, e.g. Poorly designed, operated or maintained air-handling systems and dust extraction systems Inadequate procedures for, and movement of personnel, materials and equipment Insufficiently cleaned equipment

9. Contamination Contaminant from Environment Operators Contaminant from Equipment Cross Contamination Product from Environment Operators Product from Equipment CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING CROSS CONTAMINATION

10. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING REGULATORY ESSENCE (i) ICH vs NAFDAC cGMP ICH Q7 4.40: Containment : Dedicated production area, which can include facilities, air handling equipment and or process equipment, should be employed in the production of highly sensitizing materials such as penicillins or cephalosporins

11. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING REGULATORY ESSENCE (ii) • NAFDAC Good Manufacturing Guidelines for Pharmaceutical Products 2016 was very specific on use of dedicated and contained facility for beta lactam production. • NAFDAC GMP guidelines section3.46: The manufacture, processing and packaging of highly sensitizing materials such as beta lactams or biological preparations such as live micro-organisms , highly active products such as some antibiotics, hormone,, cytotoxics substances and technical poisons such as pesticides and herbicides should be carried out in a dedicated facilities to prevent cross contamination.

12. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING REGULATORY ESSENCE (iii) • NAFDAC cGMP guidelines 2016, Section 6.20: Further emphasis on use of dedicated facility and the prevention of contamination and cross contamination Contamination of a starting material or a product by another material or product must be avoided……………………….. Amongst the most hazardous contaminants are the highly sensitizing materials (beta lactam )etc…….. should be manufactured in dedicated facility.

13. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING REGULATORY ESSENCE (iv) • NAFDAC cGMP guidelines 2016 Section 6.21: ………the outcome of the quality risk management process should be the basis for determining the necessity for and extent to which equipment and facilities should be dedicated to a particular product or product family. This may range from dedicating specific product contact parts to dedication of facility. It may be acceptable to confine manufacturing activities to a segregated , self contained area within a multipurpose facility where justified. ICHQ7:4.40 and NAFDAC GMP guidelines ;same inclination.

14. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING POTENTIAL HEALTH CONSEQUENCES • Beta lactam chemical manufacturing processes includes but not limited to fermentation and synthesis may create beta lactam intermediate or derivatives with unknown health consequences • Some beta lactam antibiotics may have no potential for cross reactivity with beta- lactam of other classes whereas some may exhibit sensitizing activities as derivatives before the incorporation of side chains that confers antibacterial activity

15. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING BASIC MOLECULAR STRUCTURE OF BETA LACTAM

16. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING CONTROL GUIDANCE • Controls are required for both beta – lactam API (ICH Q7 :4.40) and Finished Pharmaceutical Products (FPP) manufacturing ( required to comply with cGMP regulation 21CFR part 210 and 211. • As regulatory requirement NAFDAC recommends following the relevant portions of NAFDAC cGMP guidelines 2016 for Beta-lactam FPP. manufacturing • In addition manufacturers can ensure containment and prevent cross contamination during production by following current good Manufacturing practices(cGMP)

17. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING MANUFACTURING cGMP (i) • Most cGMP focuses on controls measures for containment that directly address • Facility • Equipment • Processes • Personnel • Materials • cleaning to prevent cross contamination/contamination or mix up during manufacturing , processing , packaging, storage and holding

18. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING MANUFACTURING cGMP (ii) • Separate or defined manufacturing areas • Control system necessary to prevent cross contamination and mix ups • Requirement to test non-penicillin drugs product for penicillin ( when there is possibility of exposure to cross contamination exists) and prohibits manufacturers from marketing such products if detectable levels of penicillin are found

19. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING MANUFACTURING cGMP (iii) • Manufacturers must completely separate air handling system for Beta lactam ( penicillins and non penicillin beta lactams) from those used for other drugs for human use.

20. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING ASSESSMENT OF FACILITY • There can be a building within a building , however every aspects of operation must be separate including physical barriers and separate air handling units • Manufacturing restricted to a specific class of beta lactam compound/ product ( eg cephalosporins) would generally not mandate separate facility or air handling systems and could permit production campaign • Need well established written procedures ad controls.

21. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING CONTAINMENT • What is containment? A process or device to contain product , dust, or contaminants in one zone , preventing it from escaping into another zone • Containment may either be adequate or inadequate: • Adequate containment • Inadequate containment

22. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING CAUSES OF INADEQUATE CONTAINMENT Poor or inadequate containment controls results from the following: • Mechanical transfer operators, materials, interchanging /alternation of equipment between two or more process areas Activity gowns/clothing and non product contact surfaces • Airborne Transfer (open operations, spills, leakage) Uncontrolled release of gases, dust, vapours , sprays from materials and products in process. Migration of airborne particles throughout facility

23. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING CAUSES OF INADEQUATE CONTAINMENT • Residues on equipment (product contact surfaces) • Resulting from multi-use : residue from previous production activity • Dedicated equipment: degradation (build up and lack of cleaning) • Mix up • Inadequate design of facility and equipment • Inadequate process( procedural) controls

24. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING DRIVERS OF CONTAINMENT FAILURE • Failure of containment controls can cause cross contamination from one place or product to the adjacent area by • Personnel • Equipment • Materials • Inadequate facility design • Poor procedures and unguided/ uncontrolled activities

25. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING MAJOR CHALLENGES (i) The major challenges in designing , manufacturing and packaging beta lactam facilities are as follows • How to physically and functionally isolate ß-lactam facility from adjacent facilities • How to design the man and material flow for handling and processing the non- ß- lactam products • 3. How to design the HVAC, spillage and decontamination system

26. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING MAJOR CHALLENGES (ii) • How to detect measure and avoid cross contamination? • How to control process waste and how to dispose off the same safely.

27. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (i) • Containment monitoring programme appropriate for manufacturing ß- lactam products in conjunction with non beta lactam products and among non penicillin ß – lactam product • Dedicated facility and AHU for manufacturing each class of beta lactam antibiotics • When beta lactam and non beta lactam production occurs in the same building the penicillin area must be structurally and functionally isolated

28. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (ii) • Nothing shall be common between the two facilitates • Proper procedures to restrict spillage, dusting and occupational health hazardous from ß-lactam products are undertaken. • Close monitoring of gowning , sampling, weighing, mixing, filling and packing of ß-lactam product for likely cross contamination of other products

29. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (iii) • Validate LAF hoods and filter systems used for handling ß- lactam products • Ensure adequate and efficient decontamination of vessels, equipment, machines used for processing ß-lactam products • Ensure the air locks , change rooms , pass boxes are robust construction to avoid cross contamination of ß-lactam products

30. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (iv) • Ensure that entry and exit doors, materials and personnel have an interlock mechanism to prevent the opening of more than on door at a time • Ensure that the man/material entry and exit facilities are independent • The exit side must incorporate air shower to take off beta lactam from the operator body

31. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (v) • Ensure that the facility is maintained at a negative air pressure to the environment . This will restrict environmental contamination with ß-lactam drug residue • Ensure that the premises ( and equipment) are appropriately designed and installed to facilitate batch to batch cleaning and decontamination • Ensure that the man and material flow is properly designed to avoid undue exposure and spreading of the beta lactam residue

32. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (vi) • Ensure that the activities carried out in the vicinity of the site are closely monitored for likely contamination • Ensure that the HVAC outlets of the ß- lactam section does not cross match with the HVAC inlet of non beta lactam facility • Ensure that the ß- lactam facility is a well – sealed structure with no air leakage through ceiling , service penetration door, window and ventilators.

33. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (vii) • Ensure that HVAC system is appropriately designed and maintained to ensure protection of products, personnel and the environment from beta lactam residue • The direct venting of the air to the atmosphere is strictly prohibited • Ensure that there is adequate light in the facility to indicate deposition of residues on walls, roof and machines in place • Ensure that the air is exhausted outside through HEPA filters and not recirculation except to same area and provided that further HEPA filtration is use

34. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (viii) • Ensure that where possible single -pass air handling system with no re-circulation are provided. • Ensure airlocks and pass through hatchets are effectively covered by AHU to provide necessary air pressure cascade and containment • The final airlock or pass through hatch bordering on non GMP areas should be at a positive pressure to prevent ingress of contaminants into the facility • Ensure operators leaving the containment areas pass through air showers to remove dust particle from their garment

35. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (ix) • Ensure that HEPA filters in the HVAC system are terminally mounted to avoid cross -contamination from backflow in the event of a supply air flow failure. • Ensure that biosafety cabinet or glove boxes are used to handle highly potent beta lactam products • ensure that air supplies in the facility conform to international standards and is consistent with the zone concept and the product specific protection requirements.

36. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (x) • Conduct risk analysis for potential cross contamination of the non beta lactam product from betam lactam or contamination of one beta lactam product with other beta lactam product • Do ensure that the exhaust system are protected from(with) two bank of HEPA filters in series. • Ensure that filter leakage test should be performed in accordance with ISO 14644-3

37. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (xi) • Ensure that all contaminated filters are suitably disposed off and records are maintained • Ensure that all portable vacuum cleaners, portable dust collector are fitted with HEPA filters • Do ensure that the operators are fully decontaminated during entry and exit through overhead and lateral air shower operating at high speed. • Ensure that air showers are subjected to appropriate qualification • Ensure that liquids and solid waste are suitably disposed to avoid environmental contamination

38. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (xii) • Ensure that all air exhaust points are located as far as possible from air entry points in the facility • Design beta lactam and non beta lactam facilities separately • Further avoid common entrance , stores and packaging and dispatch areas • Don’t appoint common QA personnel for collecting samples. • Restrict movement of staff from beta lactam areas or facility to non beta lactam areas( separate operators)

39. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (xiii) • Check that walls, roofs and machine surfaces are regularly monitored for residual amounts of beta lactam products • Ensure that the organizational structure , procedures , processes , resources and activities are adequate to maintain integrity of beta lactam products • There should be dedicated storage areas for beta lactam actives and finished products. • Conduct cross contamination audit and annual cross contamination reviews

40. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING TECHNICAL CONTROL MEASURES FOR CONTAINMENT (xiv) • Maintain MSDS for all beta lactam materials /products • Use monolithic epoxy coated floorings in all core production areas to discourage deposition of beta lactam dust on floor. • Insulate all doors , windows, hatches for possible leakage of beta lactam residues

41. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING CONTAINMENT DESIGN FOR EQUIPMENT Closed material discharge system ( dust containment)

42. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING direction of material flow Containment installation in pharmaceutical manufacturing- material transfer

43. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING CONDUCTING RISK ANALYSIS FOR CROSS CONTAMINATION Conduct a risk analysis of cross contamination: • Possibility of exposure ( material exposure points to environment during processing • Air-bone and mechanical transfer ( needed containment for personnel, equipment and materials) • Facility design characteristics ( Flow and operation adequacy of HVAC system • Campaign production - for beta lactam and non beta lactam products ( not acceptable as cleaning procedures do not include air handling system and other surfaces throughout the facility).

44. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING CONTAINMENT MONITORING (i) • Should be such that will demonstrate containment of beta lactam • A plan should be put in place to include periodic sampling( representative sampling plan, procedures for containment control , product testing; analytical procedures and surface sampling techniques, product testing(suspected cross contamination or annual plan) • Maintain a risk register/log

45. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING CONTAINMENT MONITORING (ii) • Representative sampling plan; to detect undesired residue in production areas (worst case) • Containment control procedures : SOPs( mechanism, controlling, determining and correcting deficiencies) • Investigations( severity, root cause, corrective action and need for product testing) • Personnel , machine and material movements.

46. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING CONTAINMENT MONITORING (iii) • Analytical and surface sampling techniques ( should be able to demonstrate control of undesired beta lactam in separation within the specified area, product contamination, decontamination of equipment and facilities. • Product testing to determine the level of contamination within a batch ( suspected possibility of product contamination/ test product prior to sales. • Any detectable level of penicillin is considered violative irrespective of test sensitivity (LOD) and action levels established

47. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING CONCLUSION Appropriate containment measures should always be established and implemented in a beta lactam manufacturing plant/facility to prevent cross contamination from personnel, facility, material etc, and also the untowards effects/health issues that may be associated .

48. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING REFERNCES • NAFDAC GMP Guidelines for Pharmaceutical products 2016 • GMP Guideline ICH Q7 ,Good Manufacturing Practice for Active Pharmaceutical ingredients • Tips for Designing , Manufacturing, Packaging and monitoring beta lactam facilities. ,By R.M Gupta • WHO workshop on the containment of World Health organization(2004)

49. CONTAINMENT CONTROLS IN BETA LACTAM MANUFACTURING

50. CASE STUDY 1 An OSD and Dry syrup manufacturer is a registered supplier of some essential drugs to a state facility and major markets in the country. Currently the following scenarios exist in the facility : Manufactures both beta lactam and non beta- lactam products under the same facility. The company is equipped with an HAVC systems that operates on re-circulated air supply to core production areas with a secondary filter final installation. The company maintains one storage warehouse for all APIs used in manufacturing . Physical barriers and separation of manufacturing of beta lactam product from other product in same building was in place . Room space monitoring gauges were in place with some value excursions for mixing and filling areas . Also the operatives were seen exiting from the facility through the same gowning areas during their break hour. Justify why products from the company should be accepted or not.