The flaws in new Schedule M

                                                        -          Ganadhish Kamat

Introduction -

CDSCO had issued Draft Schedule M vide GSR 999(E) in 2018 for inviting comments from the stakeholders. Since the Schedule was getting revised after 17 years, I personally went through the entire document and provided exhaustive comments to CDSCO as individual as well as through the company I was working with and through IPA. I am sure many others also must have painfully gone through the documents and provided comments in view of making the document better and as scientific and flawless as possible. When draft is published for comments, it is fair to expect that, comments received will be collated and evaluated and if found logical incorporated into final document. Even a workshop with the stakeholders could have been good idea to better understand logic behind the suggestions / comments and to resolve any doubts. Unfortunately, this process was not followed by the agency which expects industry to follow the processes. This is evident from the fact the final document issued vide GSR 922(E) on 28^th December 2023 is identical to the draft issued 5 years back. The preamble in the document however states that all comments received from stakeholders were considered and incorporated as appropriate. Now the questions arise, if CDSCO did not have intention of considering the comments from stakeholders, why were they requested in first place? Why it took 5 years to issue final version if no changes were made? Anyway, since none of the comments were accepted, the final document has many glaring flaws. I have only captured the major ones in this article.     

General Comments–

The title of the document is “GOOD MANUFACTURING PRACTICES AND REQUIREMENTS OF PREMISES, PLANT AND EQUIPMENT FOR PHARMACEUTICAL PRODUCTS”. Good manufacturing Practices covers all the aspects of pharmaceutical operations including Facility and Equipment, Materials, Production, Packaging and Labelling controls, Laboratory system (QC) and Quality systems. Hence there was no need for specifically calling out Premises, Plant and Equipment. Secondly the term Pharmaceutical Product is typically used for Drug product. Term Drug substance or API is used to refer to Active Pharmaceutical ingredients.

The guideline is written in the style of book explaining relevance of different controls and theoretical aspects of certain equipment etc which should not be part of rules. For example, there is lot of technical information like HVAC design elements (including cost aspects) etc which should not be part of schedule to drug law. Many of the requirements are too prescriptive and may not be required to achieve required controls. Manufacturers should have flexibility of using alternate approaches as long as desired controls are achieved. The document is too detailed and over-prescriptive about how to achieve certain things rather than specifying what is required. This will restrict manufacturers from adopting alternative or new technologies which can achieve same or better results.

Some content is not logically arranged. There are lot of repetitions which could have been eliminated thereby making the document concise. Many of the requirements given under specific dosage forms are already covered in the main part and some although mentioned under specific requirements are common for other dosage forms too and hence should have been in main part. There are some requirements which are technically correct but will be difficult to implement and will increase cost without significant benefit. For example if each of > 10000 units have to set up PV function, it will result in huge cost. Reporting of ADEs in India is dismal. Even in big companies, I was associated with, we were receiving less than 10 ADEs in a year. So setting up PV for MSMEs may not help much. Secondly even if we consider average of 20 products per company, total products distributed in India will be around 200,000. If these many PDURs are submitted by all these manufacturers in a year, does CDSCO/IPC has capacity to process them? Since IPC already does case processing for ADEs received from PV centers, it might be better that smaller companies are allowed to only report ADEs to IPC and can be exempted from other requirements such as case processing and reporting. 

Specific issues –

1.       Section 6 (Complaints and Adverse events) requires person responsible for Quality control (QC) shall normally be involved in review of investigations. Investigations are typically reviewed and approved by Quality Assurance. This problem of Using term Quality control in place of Quality Assurance or Quality unit persists throughout the document.

2.       Section 8 (Change control) requires evaluation of the first batch produced or tested under the change, after the change has been implemented. This is meaningless because all batches irrespective of change needs to be evaluated. Secondly all changes are not product specific.

3.       Section 10 (Self inspections, quality audits, supplier’s audit and approval) states the purpose of self-inspection is to evaluate the manufacturer’s compliance with good manufacturing practices in all aspects of production and QC. This is incorrect. The self inspection should evaluate all 6 systems, namely Facility & Equipment, Manufacturing, Packaging & labelling controls, Materials, Quality control (Laboratory) and Quality. The section also states “Self-inspections shall be performed routinely, and may be, in addition, performed on special occasions e.g., in the case of product recall or repeated rejections, or when an inspection by the regulatory authorities is announced”. Self-inspection cannot help in addressing issues like recalls and rejections. Detailed investigations and RCA is required to address them. The section also separately mentions Quality Audits to be performed using external consultants. This should not be part of rules. It should be left to the manufacturer to decide whether they want to use external consultants. The section also mentions the person responsible for Quality control shall be responsible for approving vendors. This is typically done by Quality Assurance.

4.       Section 11 (Personnel)- Sub-section 11.3.1 states “Key personnel include the heads of production, the head(s) of quality unit(s) and the authorized person.” There are multiple people in a factory authorized to perform various tasks. This statement is not clear about what “Authorized person means”. 

Sub-section 11.3.9(e) requires "any planned changes or deviations in manufacturing or QC have been notified in accordance with a well-defined reporting system before any product is released. Such changes may need notification and approval by the licensing authority". As there is no system of notifying and approval of product related changes by licensing authority, this clause can not be complied with. (Similar clause about review of dossier variations submitted, granted or refused is included under 2.3.2(f) although such system doesn't exist)

Sub-section 11.3.9 (h) requires person releasing the batch to verify appropriate audits, self-inspections and spot-checks are carried out by experienced and trained staff. This check is not relevant for the batch release. There are also many other irrelevant requirements in the section all of which have not been listed here.

5.       Section 12 (Premises)- sub-section 12.3.2 states “Toilets shall not communicate directly with production or storage areas.” Sub-section 12.4.4 stipulates access control only for quarantine area, actually it is required for entire warehouse. Sub-section 12.5 stipulates weighing of starting materials and the estimation of yield by weighing to be carried out in separate weighing areas. As the yield determination is done in the manufacturing and not in warehouse, this statement makes no sense.

6.       Section 14 (Materials)- Sub-section 14.26 requires all containers and closures and packaging materials intended for use in pharmaceutical packaging to comply with the pharmacopoeial requirements, although the pharmacopoeial standards do not exist for many types of containers and closures. Sub-section 14-34 states “The need for additional testing of any finished product that has been reprocessed, reworked or into which a recovered product has been incorporated, shall be considered by the QC department”. First of all, reworking, reprocessing and adding recoveries should not be allowed in finished dosage forms unless the process is validated and stability & equivalence has been established. The decision about any additional testing should be taken by QA or Quality unit and not be QC. (In many places document mentions QC where either QA or Quality unit should be mentioned).

7.       Section 17 (Documents)- Sub-section 17.3.1.2 lists out labelling requirements for finished products. Since there is separate section on labelling requirements in Drug rules, there is no need for including these requirements in Schedule M. Subpoint (g) under this subsection requires printing the name and address of the manufacturer or the company and the person responsible for placing the product on the market on the label. This is absolutely ridiculous because it serves no purpose and it is not clear who should be considered as the person responsible for placing the product in market. Sub-section 17.3.3.4 which requires documents describing testing procedures to state the required frequency for re[1]assaying each starting material as determined by its stability is impractical. Many starting materials especially the excipients do not have stability indicating test methods. Subsection 17.3.5.1 requires description of pack and directions for sampling to appear in the specification. This is not required as different companies describe in other documents.

8.       Section 19 (Good practices in Quality Control) – Sub-section 19.4.1 (C) mentions ensuring the correct labelling of containers of materials and products to be responsibility of QC. It should be either of QA or of Quality unit. Sub-section 19.7.4 requires supplier’s Certificates to be originals (not photocopies) or otherwise have their authenticity assured. It is not always possible to get original certificate especially in case of excipients where one lot is supplied to large number of manufacturers. The clause of “authenticity assured” is subject to interpretation. Sub-section also mentions that the supplier’s COA should include signature of the competent official and statement of his or her qualifications. It is not common practice to mention qualification on the COAs. Most vendors (especially international) don’t change the formats for specific country needs unless it is logical.  

9.       Part II Section 4.3 mentions that the velocity at working level shall not be less than 0.36 m/s. If the level of exposure of product is considered as working height, velocity of 0.36m/s can not be achieved due to resistance from working surfaces.

10.   Part VIII (Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) All ingredients for a dry product shall be sifted before use unless the quality of the input material can be assured. Such sifting shall normally be carried out at dedicated areas. Dedicated area is not required for this operation. It may not be possible to sift some materials like polymers, liquids, waxes etc which can be used in OSD (Oral Solid Dosage). It also requires the corridor shall be maintained at a higher pressure than the cubicles, and the cubicles at a higher pressure than atmospheric pressure. There are various ways of achieving control of cross-contamination, for example both corridor and room can be at same pressure with bubble or sink type airlock separating two. Such specific recommendations can limit use of different options and may not be suitable for certain class of drugs. Highly potent products are recommended to be manufactured under a pressure cascade regime that is negative relative to atmospheric pressure. This is not required if there is adequate filtration in the return air or exhaust. Keeping the pressure negative may result in sucking of unclean air from surrounding if there are even minor gaps. The statement “Room pressure differential between adjacent cubicles, which are linked by common dust extraction ducting, shall be avoided” makes no sense. Requirement for establishing Alert / Action levels for the pressure differentials, temperature and humidity in OSD is overdoing. What one is supposed to do if alert level or action level is exceeded? Sub-point 2.4 states “Filter bags fitted to fluid-bed-drier shall not be used for different products, without being washed in between use.” This is unacceptable, because filter bags due to their woven nature are difficult to clean and should be dedicated for all types of drugs.

11.    Part IX (Specific requirements for Liquid orals) sub-section 2.8 states “Arrangements for cleaning of containers, closures and droppers shall be made with the help of suitable machines/devices equipped with high pressure air, water and steam jets.” This not applicable for all type of containers and closures. Sub-section 3.1 prescribes limit of 100 cfu for total count (not clearly mentioned) and absence of pathogens. Many organisms may be pathogenic or opportunistic pathogens but may not cause problem when level is low in different routes of administration. It is not possible to demonstrate absence of all pathogens and also not required. Sub-section 3.2 requires flushing of water after any chemical sanitization of the water system to ensure that the sanitizing agent has been effectively removed. This is not relevant in case of Ozone sanitization as it gets destroyed by UV. Sub-section 4.2 prohibits carrying of materials likely to shed fibre like gunny bags, or wooden pallets into the manufacturing area. This requirement is applicable for all the products and not just liquid orals.

12.    Part X (Specific requirements for Topical products) requires heating of vehicles and a base like petroleum jelly to be done in a separate mixing area. This is not necessary.

13.    Part XI (Specific requirements for MDIs). Many of the requirements prescribed are not specific to MDIs, some are too prescriptive and irrational. Mentioning of current available technologies in regulations is not appropriate.

14.    Part XII (Specific requirements for APIs) – This part gives all the requirements pertaining to API manufacturing and is in line with ICH Q7. However the Note at the beginning of the chapter says “Good Manufacturing Practices for pharmaceutical products: main principles as given in Part I of this Schedule shall be complied for the manufacture of Active Pharmaceutical Ingredients in addition to these requirements”. Some requirements given in Part 1 especially related Premises, storage areas, water, sampling of starting materials etc may not be fully applicable for APIs. This is likely to create confusion. This section allows three approaches of process validation namely Prospective, Concurrent and Retrospective. Retrospective is no longer being used. All validations should be completed before release of the batches. Under rare circumstances, such as very low requirement or drug shortage etc, concurrent release may be allowed with appropriate controls. There are also unscientific statements such as “Process validation shall confirm that the impurity profile for each API is within the limits specified. The impurity profile shall be comparable to or better than historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies”. Process validation should demonstrate ability of the process to consistently produce desired quality. It should demonstrate consistency within the batch and in between the batches apart from compliance to specifications.

-          Part XIII (REQUIREMENTS OF PLANT AND EQUIPMENT)- Since all the requirements are already specified in Part I and in product specific parts, this section serves no purpose. The Part includes some irrational requirements and specifies certain technologies which can prevent the manufacturers from using alternative technologies which can produce same result. For example, in Section 11 (Parenteral preparations) different types of products and technologies are listed and equipment required for them, but there is no consideration of Pre-filled syringes, use of pre-sterilized packaging components such as vials, rubber bungs etc, lyophilized products. Only RO, EDI and multicolumn distillation unit (with heat exchanger) have been recommended for generation of purified water and WFI. There is no reason why other technologies like Ion exchange resin cannot be used for making purified water followed by distillation using single column or multicolumn distillation unit to obtain WFI. Also, there is no mention of vapor compression technology which is now becoming popular. There is also no mention of pure steam generator which is critical for generating pure steam required for Steam sterilization.

Conclusion –

This document is a good improvement over the previous version issued in 2001 and will help in improving the quality of the drugs sold in India. However, it could have been lot better if CDSCO had shown some openness of accepting feedback from the stakeholders. While the CDSOC is working towards improving the quality of drugs, the quality of this document is not something to be proud of.