Equipment Cleaning Validation for Active Pharmaceutical Ingredients (API)
Introduction
This procedure provides guidance in the validation of cleaning processes for equipment used in the manufacture of Active Pharmaceutical Ingredients (API).
Definitions
Acceptable Daily Intake (ADI) – an amount of a substance administered or consumed on a daily basis that will not produce a pharmacological or toxic response.
Summary
1. A Cleaning Evaluation should be conducted, documented, and approved by the Site Quality Authority and Production Team. This evaluation may be a single report or several reports and may be equipment centric or process centric and document or reference the required information. The purpose of this documentation is to justify the decisions made in developing the cleaning validation protocols. This evaluation should determine or consider for each equipment unit:
What material(s) are being cleaned -include consideration of at least the following items (see Table 1):
- Process Intermediates;
- APIs;
- Raw Materials;
- Cleaning and sanitizing agents;
- Solvents;
- Bacterial Endotoxins, when applicable; and
- Microorganisms, when applicable;
What residues will be tested for;
Solubility of residues in cleaning agents (including cleaning and rinse solvents);
Cleaning parameters and applicable ranges (e.g., concentrations, temperatures, times);
Cleaning method (e.g., sprayball, flooding, power hosing);
Extent of equipment disassembly;
Residual acceptance criteria;
Sampling method(s) to be used;
Potential for degradation by-products or conversion products;
Stability of material(s) being cleaned under the proposed cleaning conditions;
Suitability of the cleaning agent(s) for the materials of construction of the equipment;
Equipment surface finish (e.g., stainless steel, glass, polypropylene);
Rationales for decisions on which materials to test, the limits for testing, and the method of verification (see Table 1); and
Evaluation of campaign length.
2. Equipment with the Same Design and Operating Principle may be grouped for the purpose of validation. These groupings should be documented and justified. The documentation should be approved by Site Quality Team and Production Team. If equipment grouping is used, cleaning validation should be performed using three executions of the same cleaning procedure using any combination of equipment within a group.
3. Where Equipment is Used to Produce Only Early Intermediates (i.e., intermediates produced prior to the introduction of the API starting materials), cleaning verification is required. Validation of the cleaning procedures for these cases is not required (see Table 1).
4. Selection of The Most Difficult To Clean Product or Process requires consideration of, at least, the following:
- Solubility of residues in cleaning agents (including cleaning and rinse solvents);
- Potential for polymers, or other side products to form during or prior to the cleaning operations;
- The Residue Acceptability Limit (RAL) required for cleaning;
- Processing Parameters (e.g., high temperature, use of carbon); and Cleaning history.
- Selection of the most difficult to clean product or process should be documented in the validation protocol or a Cleaning Evaluation Report.
5. Rinsate Method – if a rinsate method is used as the sampling method, a measured volume of solvent used for the final rinse should thoroughly wet all product contact surfaces, and should be circulated through all product contact lines before the rinsate is tested in the laboratory for residues.
6. Swabbing Method – if swabbing is used as the sampling method, swabbing of product contact surfaces should be performed in locations from which there is a likelihood of transfer of residue to a subsequent product and from most difficult to clean areas (i.e., dead-legs, bottom valves, overheads, tank domes and inlets).
7. Rinsate Recovery Studies can be based on worst case product groupings, and/or by grouping of worst case materials of construction.
8. The Maximum Allowable Residue (MAR) Based on Therapeutic Dose should be calculated for each therapeutic product including clinical products (where dose information is available) that is to be processed in a specific equipment unit, and should be determined by the formulas and equations provided in Appendix I. The MAR based on toxicity should be determined by use of the formulas and equations provided in Appendix I. The Dose MAR (where applicable) and the Tox MAR (where applicable) should be calculated and compared against the weight percent limit MAR from Table 1 and the lowest of the three selected to calculate the RAL. If a worst case limit is used for equipment producing multiple compound types (e.g., final APIs and early intermediates), the most conservative limit for all compound types produced in the equipment should be selected. The limit for each compound or product, “A” may be calculated and used for a specific subsequent product, “B”, or a worst case limit for all A/B Combinations may be used.