COMMENTS ON REVISED DRAFT OF SCHEDULE M PUBLISHED IN 2018 THROUGH GSR 999E

 

                           

 

                          - Ganadhish Kamat

General Comments :-

This document is largely based on book “Quality assurance for Pharmaceuticals” released by WHO. While the books are written with the intention to provide information including how to do certain things, the law should focus on defining clear expectations without being restrictive / prescriptive about how to achieve those expectations.    

• While most of the recommendations are in right directions and significant improvement over current Schedule M, the document is too detailed and prescriptive to be Schedule of drug law.
• There are lot of repetitions which can be eliminated thereby reducing length of the document. 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. In view of this all such duplications and contradictions should be deleted / corrected. 
• Some content is not logically arranged. (PICS guideline has more logical arrangement which might be adopted)
• 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 these are too prescriptive and may not be required to achieve expected controls. Manufacturers should have flexibility of using alternate approaches as long as desired controls are achieved. 
• While the title says this is Good Manufacturing Practices for Pharmaceutical products, it is not clear whether it is applicable for Drug products or also to API manufacturing. It will be good to include section describing applicability. 
• Part XII covers all the requirements of ICH Q7 and hence this can be used as standalone GMP requirement for API and not in conjunction with Part 1. Besides some of the requirements described in Part 1 related to Premises, Water, storage of materials, sampling etc are not applicable for APIs. In view of this whole schedule M should be divided into two main parts one of Drug products and other for API. 
• I suggest inclusion of Glossary to clearly define some of the terms which is necessary for correct legal interpretation.

Specific comments on the draft document 

S. No.	Section/Page No.	Draft guidance statement	Recommendations/Suggestions/Concerns
1)	Page No 7, Point No. 6.5	Complaints: Any complaint concerning a product defect shall be recorded with all the original details and thoroughly investigated. The person responsible for QC shall normally be involved in the review of such investigations	Suggest replacing QC by Quality unit as such review can be done by QC or QA based on the org structure.
2)	Page No 7, Point No. 7.11, 7.12 & 7.13	Product Recalls: 7.11. The distribution records shall be readily made available to the persons designated for recalls. 7.12 The designated person shall record a final report issued, including reconciliation between the delivered and the recovered quantities of the products 7.13 The effectiveness of the arrangements for recalls shall be evaluated from time to time.	These sections are repeated earlier in 7.6, 7.7 & 7.8
3)	Page No 8, Point No. 8.6	Change Control: After the change has been implemented there shall be an evaluation of the first batches produced or tested under the change	This sentence to be deleted as many changes may not be related to manufacturing process. Secondly all the batches are anyway evaluated (tested) prior to release, so there is no need for such clause. It is confusing "what is meant by evaluation".
4)	Page No 9, Point No. 9.5	Contract	As the contract is referred earlier, it might logical to move this section earlier.
5)	Page No 10, Point No. 9.5.2	Contract : The contract must clearly state the way in which the authorized person, in releasing each batch of product for sale or issuing the certificate of analysis, exercises his or her full responsibility and ensures that each batch has been manufactured in, and checked for, compliance with the requirements of the licence.	Earlier clause states that all the responsibilities shall be clearly laid down so there is no need for this clause defining release
6)	Page No 10, Point No. 10.1	The purpose of self-inspection is to evaluate the manufacturer’s compliance with good manufacturing practices in all aspects of production and QC.	Self-inspection should cover all the functions associated with manufacturing including, warehouse, engineering, Quality assurance etc. and should not be restricted to Manufacturing and QC.
7)	Page No 10, Point No. 10.1	Self-inspections shall be performed routinely, and may be, in addition, performed on special occasions, e.g. in the case of product recalls or repeated rejections, or when an inspection by the regulatory authorities is announced.	Suggested deleting this. Sites should be all time ready and not specially prepare for inspections. Secondly, self-inspection is not good tool for solving problems like recall or repeated rejections. For those issues, focussed investigations are required.
8)	Page No 11, Point No. 10.7	Quality audit	Quality audit and self-inspections are same and should not be included as separate activity.
9)	Page No 11, Point No. 10.8.1	Suppliers’ audits and approval: The person responsible for quality control shall have responsibility, together with other relevant Departments, for approving suppliers who can reliably supply starting and packaging materials that meet established specifications.	Quality Control should be replaced by Quality Unit
10)	Page No 12, Point No. 11.3.1	Key personnel: Key personnel include the heads of production, the head(s) of quality unit(s) and the authorized person. The quality unit(s) typically comprise the quality assurance (QA) and quality control (QC) functions. In some cases, these could be combined in one department. The authorized person may also be responsible for one or more of these quality unit(s).	People in various functions and at various level are authorized to perform specific tasks which are defined in their job descriptions. So there is nothing like separate Authorized persons. This should be deleted.
11)	Page No 14, Point No. 11.3.9, sub point (h)	Key personnel: appropriate audits, self-inspections and spot-checks are carried out by experienced and trained staff;	Self-inspection cannot be part of batch  release
12)	Page No 14, Point No. 11.3.9, sub point (i)	Key personnel: approval has been given by the head of quality control	No separate approval is required by head of QC
13)	Page No 16, Point No. 14.3.2	Ancillary areas: Toilets shall not communicate directly with production or storage areas.	The sentence to be changed to "Toilets shall not be directly connected to production or storage areas"
14)	Page No 17, Point No. 14.4.3	Storage areas: Receiving and dispatch bays shall be separated and shall protect materials and products from the weather.	This requirement for separate receiving and dispatch bay should be deleted as it does not provide any additional protection/assurance
15)	Page No 17, Point No. 14.4.4	Storage areas: Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorized personnel. Any system replacing the physical quarantine shall give equivalent security	Access to entire warehouse should be to authorized personnel. So this specific requirement for restricted access to quarantine area is not required.
16)	Page No 17, Point No. 14.5	Weighing areas: The weighing of starting materials and the estimation of yield by weighing shall be carried out in separate weighing areas designed for that use, for example, with provisions for dust control. Such areas may be part of either storage or production areas.	Yield estimation is done in manufacturing area so separate weighing area is not required for this activity. This part to be deleted.
17)	Page No 20, Point No. 16.11	Materials: Damage to containers and any other problem that might adversely affect the quality of a material shall be recorded and reported to the QC department and investigated	To be changed to Quality unit
18)	Page No 20, Point No. 16.13	Materials: where appropriate, an expiry date or a date beyond which retesting is necessary. When fully validated computerized storage systems are used, not all of the above information need be in a legible form on the label.	This should be separate statement and should not be part of subsection (d)
19)	Page No 20, Point No. 16.15	Materials: The raw materials other than Active Pharmaceutical ingredients, if released by Quality Control Department without specific batch testing, for use in manufacturing, it shall be based on vendor approval and statistical data analysis of earlier test results of such material for release.	Use of vendor certificate of analysis in lieu of full testing should be allowed even in case of APIs provided adequate controls on vendor qualification & transportation are ensured. (Especially when the APIs are made by same company under same quality systems)
20)	Page No 21, Point No. 16.26	Materials: All containers and closures intended for use shall comply with the pharmacopoeial requirements. Suitable validated test methods, sample sizes, specifications, cleaning procedure and sterilization procedure, wherever indicated, shall be strictly followed to ensure that these are not reactive, additive, absorptive, or leach to an extent that significantly affects the quality or purity of the drug	Pharmacopoeial requirements do not exist for all container closures. So the sentence to be changed to "established specifications". Secondly use of validated test method for demonstrating lack of reactivity, absorptivity, leachability etc is not required for all dosage forms. The statement can be modified that suitability of container closure for maintaining product stability shall be established using validated test methods.
21)	Page No 21, Point No. 16.26.3	Materials: Packaging material to be used for pharmaceutical products shall be in accordance with the requirements prescribed in Indian Pharmacopoeia	All requirements not given in Indian Pharmacopoeia.
22)	Page No 22, Point No. 16.34	Materials: 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	Replace QC department by "Quality Unit". Reprocessing or reworking in finished product should be allowed only if such procedure has been adequately validated and stability is demonstrated.
23)	Page No 22, Point No. 16.36	Materials: Products returned from the market shall be destroyed unless it is certain that their quality is satisfactory; in such cases they may be considered for resale or relabelling, or alternative action taken only after they have been critically assessed by the QC function in accordance with a written procedure.	To be replaced by Quality unit.
24)	Page No 22, Point No. 19.3.1.2, sub section (g)	Documents Required – Labels the name and address of the manufacturer or the company and the person responsible for placing the product on the market	Putting name of person responsible on the product label is not advisable as people change the jobs.
25)	Page No 25, Point No. 19.3.2.3	Specifications and testing procedures : Each specification shall be approved, signed and dated, and maintained by the QC or QA units.	Replace QC & QA by Quality unit
26)	Page No 25, Point No. 19.3.3.4	Specifications for starting and packaging materials: Documents describing testing procedures shall state the required frequency for reassaying each starting material, as determined by its stability	It is impractical to establish stability of each starting materials. So the clause as determined by its stability should be deleted.
27)	Page No 26, Point No. 19.3.5.1, sub section (d)	Specifications for finished products : a description of the dosage form and package details;	This need not be part of specification as it may be described elsewhere as per company practices.
28)	Page No 26, Point No. 19.3.5.1, sub section (e)	Specifications for finished products : directions for sampling and testing or a reference to procedures;	This should be deleted as normally sampling is described in SOPs
29)	Page No 31, Point No. 19.3.10.15	Standard operating procedures and records: Records shall be maintained of the distribution of each batch of a product in order, for example, to facilitate the recall of the batch if necessary	While this is valid requirement, this is not logical place for the same.
30)	Page No 36, Point No. 21.4, sub section (c)	Good practices in quality control Other QC responsibilities include : ensuring the correct labelling of containers of materials and products	This is normally QA responsibility. Considering differences in org structures across organizations, I suggest use of term Quality unit in place of QC or QA.
31)	Page No 37, Point No. 21.6.6, sub section (c)	Control of starting materials and intermediate, bulk and finished products: the number of the container from which the sample has been taken;	This is not applicable for pool samples
32)	Page No 37, Point No. 21.6.6, sub section (d)	Control of starting materials and intermediate, bulk and finished products: the number of the sample;	Not relevant in all the cases
33)	Page No 37, Point No. 21.6.6, sub section (e)	Control of starting materials and intermediate, bulk and finished products: the signature of the person who has taken the sample;	Signature on the sample label may not be relevant if sampling activity is captured elsewhere. What is important to capture identity of sampler.
34)	Page No 38, Point No. 21.7.4	Test requirements: In lieu of full testing by the manufacturer, a certificate of analysis may be accepted from the supplier, provided that the manufacturer establishes the reliability of the supplier’s analysis through appropriate periodic validation of the supplier’s test results and through on-site audits of the supplier’s capabilities. Certificates must be originals (not photocopies) or otherwise have their authenticity assured.	It is not possible to always obtain original COA as same lot of starting material may be supplied to multiple manufacturers.
35)	Page No 38, Point No. 21.7.4, sub section (b)	Test requirements: signature of the competent official, and statement of his or her qualifications	It is not common practice to capture qualification in the COA, Title is more appropriate. Electronic signatures should be allowed.
36)	Page No 38, Point No. 21.8.2	Batch record review: Retention samples from each batch of finished product shall be kept for at least one year after the expiry date. Finished products shall usually be kept in their final packaging and stored under the recommended conditions. If exceptionally large packages are produced, smaller samples might be stored in appropriate containers. Samples of active starting materials shall be retained for at least one year beyond the expiry date of the corresponding finished product. Other starting materials (other than solvents, gases and water) shall be retained for a minimum of two years if their stability allows. Retention samples of materials and products shall be of a size sufficient to permit at least two full re-examinations.	While this is important clause, this is not logical place.
37)	Page No 44, Point No. 4.3, sub section ; Grade A	Manufacture of sterile preparations For the manufacture of sterile pharmaceutical preparations Grade A: The local zone for high-risk operations, e.g. filling and making aseptic connections. Normally such conditions are achieved by using a unidirectional airflow workstation. Unidirectional airflow systems shall provide a homogeneous air speed of 0.36–0.54 m/s (guidance value) at a defined test position 15–30 cm below the terminal filter or air distributor system. The velocity at working level shall not be less than 0.36 m/s. The uniformity and effectiveness of the unidirectional airflow shall be demonstrated by undertaking airflow visualization tests.	It is often not possible to achieve velocity of NLT 0.36 m/s at working height due resistance from working surfaces. What is important is smoke study should show that the air passes down and sweeps over the working area without any turbulence or eddies. Alternatively working height should be defined as 1 feet above the surface.
38)	Page No 110, Part VIII, Point No. 1.4	PART VIII Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) General: 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). Such sifting should not be made mandatory. Instead it can be stated that appropriate controls are put in place to prevent contamination with extraneous matter.
39)	Page No 111, Part VIII, Point No. 1.8	PART VIII Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) General: Correct directional air movement and a pressure cascade system can assist in preventing cross-contamination. The pressure cascade shall be such that the direction of airflow is from the clean corridor into the cubicles, resulting in dust containment.	There are various ways of achieving control of cross-contamination, so specific methodology should not be prescribed. For example both corridor and room can be at same pressure with bubble or sink type airlock separating two.
40)	Page No 111, Part VIII, Point No. 1.9	PART VIII Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) General:  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, so specific methodology should not be prescribed. For example both corridor and room can be at same pressure with bubble or sink type airlock separating two.
41)	Page No 111, Part VIII, Point No. 1.10	PART VIII Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) General: Highly potent products shall 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.
42)	Page No 111, Part VIII, Point No. 1.14	PART VIII Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) General: The pressure differential between adjacent rooms could be considered a critical parameter, depending on the outcome of risk analysis. The limits for the pressure differential between adjacent areas shall be such that there is no risk of overlap in the acceptable operating range, e.g. 5 Pa to 15 Pa in one room and 15 Pa to 30 Pa. in an adjacent room, resulting in the failure of the pressure cascade, where the first room is at the maximum pressure limit and the second room is at its minimum pressure limit.	This is not applicable if adjacent rooms are not connected by door or pass way. Secondly whether overlapping is acceptable or not depends upon against what differential pressure is measured. I suggest not prescribing such requirements which can vary based on the area and HVAC design.
43)	Page No 111, Part VIII, Point No. 1.16	PART VIII Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) General: The effect of room pressure tolerances shall be calculated and taken into consideration.	This statement is not clear.
44)	Page No 111, Part VIII, Point No. 1.17	PART VIII Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) General: The pressure control and monitoring devices used shall be calibrated and qualified. Compliance with specifications shall be regularly verified and the results recorded. Pressure control devices shall be linked to an alarm system set according to the levels determined by a risk analysis.	Alarm system should not be made mandatory for general OSD. To have such system, manufacturers will have to necessarily go for building management system.
45)	Page No 112, Part VIII, Point No. 1.23	PART VIII Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) General: Room pressure differential between adjacent cubicles, which are linked by common dust extraction ducting, shall be avoided.	The statement is not clear.
46)	Page No 112, Part VIII, Point No. 1.25	PART VIII Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) General: Adequate room pressure differential indication shall be provided so that each critical room pressure can be traced back to ambient pressure (by summation of the room pressure differentials), in order to determine the room actual absolute pressure. Room pressure indication gauges shall have a range and graduation scale which enables the reading to accuracy, as appropriate; normal operating range, alert and action limits shall be defined and displayed at the point of indication. A colour coding gauge may be helpful. Room pressure indication may be either analogue or digital, and may be represented as either pressure differentials or absolute pressures. Whichever system is used any out-of-specification condition shall be easily identifiable.	This is too prescriptive. Establishing alert and action limits for each room is not required. What do you do if alert limit is exceeded?
47)	Page No 112, Part VIII, Point No. 1.28	PART VIII Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) General: Maximum and minimum room temperatures and relative humidity shall be appropriate. Alert and action limits on temperatures and humidity shall be set, as appropriate.	Minimum limit is not required for each product and hence should not be made part of requirement. The limits should be set accordance to product requirements. Alert limit is not required. It is not going to add any value.
48)	Page No 112, Part VIII, Point No. 1.29	PART VIII Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) General: The operating band, or tolerance, between the acceptable minimum and maximum temperatures shall not be made too close. Tight control tolerances may be difficult to achieve and can also add unnecessary installation and running costs.	This is not relevant to be included in GMP guideline
49)	Page No 112, Part VIII, Point No. 1.30	PART VIII Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) General: Cubicles, or suites, in which products requiring low relative humidity are processed, shall have well sealed walls and ceilings and shall also be separated from adjacent areas with higher relative humidity by means of suitable airlocks.	As long as the humidity is maintained as desired, other controls are irrelevant. Clauses from 1.30 to 1.36 are too prescriptive to be part of GMP guideline. Same is true with many subsequent sub-clauses in this section.
50)	Page No 113, Part VIII, Point No. 1.47	PART VIII Specific Requirements for Manufacture of Oral Solid Dosage Forms (Tablets and Capsules) General: Exhaust air discharge points on pharmaceutical equipment and facilities, such as from fluid bed driers and tablet-coating equipment, and exhaust air from dust extraction systems, carry heavy dust loads and shall be provided with adequate filtration to prevent contamination of the ambient air.	Instead of saying filtration, it should be stated that appropriate controls are put in place to prevent dust getting into atmosphere. There are other methods like wet scrubbers available to achieve this.
51)	Page No 115, Part VIII, Point No. 2.3	Sifting, mixing and granulation: Critical operating parameters like time and temperature for each mixing, blending and drying operation shall be specified in a Master Formula, monitored during processing, and recorded in the batch records.	Reference to specific parameters such as time, temperature and specific operations such as mixing, blending etc should be removed.
52)	Page No 115, Part VIII, Point No. 2.4	Sifting, mixing and granulation: Filter bags fitted to fluid-bed-drier shall not be used for different products, without being washed in between use. With certain highly potent or sensitizing products, bags specific to one product only shall be used. Air entering the drier shall be filtered. Steps shall be taken to prevent contamination of the site and local environment by dust in the air leaving the drier due to close positioning of the air-inlets and exhaust.	It is not advisable to use filter bag for different products even after washing because it is difficult to demonstrate freedom from previous product contamination. No equipment should be used for different product without washing.
53)	Page No 115, Part VIII, Point No. 3.1	Compression (Tablets) Each tablet compressing machine shall be provided with effective dust control facilities to avoid cross contamination. Unless the same product is being made on each machine, or unless the compression machine itself provides its own enclosed air controlled environment, the machine shall be installed in separate cubicles.	To be deleted as it is giving wrong meaning. No two products should be allowed to be manufactured in single room even with dust control facility.
54)	Page No 116, Part VIII, Point No. 3.8	Compression (Tablets) In-process control shall be employed to ensure that the products remain within specification. During compression, samples of tablets shall be taken at regular intervals of not greater than 30 minutes to ensure that they are being produced in compliance with specified in-process specification. The tablets shall also be periodically checked for additional parameters such as ‘appearance‘, ‘weight variation‘, ‘disintegration‘, ‘hardness‘, ‘friability ‘ and ‘thickness‘ and contamination by lubricating oil.	Frequency of 30 minutes may not be required for new machines with automated controls like compaction force monitoring.
55)	Page No 116, Part VIII, Point No. 5.1	Filling of Hard Gelatin Capsule: Empty capsules shells shall be regarded as ‘drug component’ and treated accordingly. They shall be stored under conditions which shall ensure their safety from the effects of excessive heat and moisture	While many controls have been described for tablet compression, same have not been defined for capsule filling which is similar process. There is no need to specify such details in both the cases.
56)	Page No 116, Part VIII, Point No. 6.2	Printing (Tablets and Capsules): After printing, tablets and capsules shall be approved by Quality Control before release for packaging or sale.	Quality control to be replaced by Quality unit. Why this step is required specifically for printing step?
57)	Page No 116, Part VIII, Point No. 7.2	Packaging (Strip and Blister): Uncoated tablets shall be packed on equipment designed to minimize the risk of cross-contamination. Such packaging shall be carried out in an isolated area when potent tablets or Beta lactum containing tablets are being packed.	This control is required for coated tablets too as the tablets can get crushed during the operation thereby exposing the drug to environment. Suggest removing special mention of potent products or Beta lactam, because Beta lactam require segregated facility. Other potent drugs can be handled with adequate controls like campaign runs.
58)	Page No 117, Part IX, Point No. 2.8	Specific Requirements for Manufacture of Oral liquids (Syrups, Elixirs, Emulsions and Suspensions)   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.	All these may not be required for all types of containers and closures, hence instead of specifying these, it should be mentioned that appropriate controls are implemented for cleaning of container closures used in the process.
59)	Page No 118, Part IX, Point No. 3.1	Purified Water: The chemical and microbiological quality of purified water used shall be specified and monitored routinely. The microbiological evaluation shall include testing for absence of pathogens and shall not exceed 100 cfu /ml.	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. It is important to demonstrate that the organisms present are not pathogenic by intended route of administration. Typically for oral products freedom from E.Coli is required to be demonstrated.
60)	Page No 118, Part IX, Point No. 3.2	Purified Water: There shall be a written procedure for operation and maintenance of the purified water system. Care shall be taken to avoid the risk of microbial proliferation with appropriate methods like recirculation, use of UV treatment, treatment with heat and sanitizing agent. After any chemical sanitization of the water system, a flushing shall be done to ensure that the sanitizing agent has been effectively removed.	Flushing is not required in case of Ozone sanitization as it can be destroyed by UV.
61)	Page No 118, Part IX, Point No. 4.2	Manufacturing Materials likely to shed fibre like gunny bags, or wooden pallets shall not be carried into the area where products or cleaned- containers are exposed.	Such materials should not be allowed in any drug product manufacturing facility and not just for liquid orals.
62)	Page No 119, Part X, Point No. 8	PART X Specific Requirements for Manufacture of Topical Products i.e. External Preparations (Creams, Ointments, Pastes, Emulsions, Lotions, Solutions, Dusting Powders and Identical Products): Heating vehicles and a base like petroleum jelly shall be done in a separate mixing area in suitable stainless steel vessels, using steam, gas, electricity, solar energy etc.	Why separate?
63)	Page No 119, Part XI, Point No. 1	PART XI Specific Requirements for Manufacture of Metered – Dose Inhalers (MDI) There are presently two common manufacturing and filling methods as follows	Current available technologies need not be included in the drug law.
64)	Page No 120, Part XI, Point No. 3.1	Building and civil works: The building shall be located on a solid foundation to reduce risk of cracking walls and floor due to the movement of equipment and machinery	Why this is specifically required for MDIs?
65)	Page No 120, Part XI, Point No. 3.2	Building and civil works: All building surfaces shall be impervious, smooth and non-shedding. Flooring shall be continuous and provided with a cover between the floor and the wall as well as between the wall and the ceiling. Ceiling shall be solid, continuous and proceeded a cone with the walls. Light fittings and air-grills shall be flush with the ceiling. All service lines requiring maintenance shall be erected in such a manner that these are accessible from outside the production area.	The highlighted statements are not clear
66)	Page No 120, Part XI, Point No. 3.3	Building and civil works: The manufacturing area shall be segregated into change rooms for personnel, container preparation area, bulk preparation and filling area, quarantine area and spray testing and packing areas.	This is too prescriptive. Facility should have designated areas for carrying out various activities.
67)	Page No 120, Part XI, Point No. 3.5	Building and civil works: Separate area shall be provided for de-cartooning of components before they are air washed.	Too prescriptive
68)	Page No 121, Part XI, Point No. 6.2	Sanitation: Use of water for cleaning shall be restricted and controlled. Routinely used disinfectants are suitable for sanitizing the different areas. Records of sanitation shall be maintained	This is very vague statement.
69)	Page No 121, Part XI, Point No. 7.3	Equipment: All the equipment shall be suitably calibrated and their performance validated on receipt and thereafter periodically.	This requirement is common for all dosage forms.
70)	Page No 121, Part XI, Point No. 8.1	Manufacture Metering valves for aerosols are a more complex engineering article than most pharmaceutical components. Specifications, sampling and testing shall be appropriate for this situation. Auditing the Quality Assurance system of the valve manufacturer is of particular importance	This should not be part of manufacturing.
71)	Page No 121, Part XI, Point No. 8.5	Manufacture The valves shall be carefully handled and after de-cartooning, these shall be kept in clean, closed containers in the filling room.	Too prescriptive. Why the valves cannot be stored in another clean area instead of filling room? Appropriate place is better term.
72)	Page No 121, Part XI, Point No. 8.6	Manufacture Containers and valves shall be cleaned using a validated procedure appropriate to the use of the product to ensure the absence of any contaminants such as fabrication aids (e.g. lubricants) or undue microbiological contaminants. After cleaning, valves shall be kept in clean, closed containers and precautions taken not to introduce contamination during subsequent handling, e.g. taking samples. Containers shall be provided to the filling line in a clean condition or cleaned on line immediately before filling.	This is covered in previous clauses.
73)	Page No 122, Part XI, Point No. 8.8	Manufacture In-process controls shall include periodical checking of weight of bulk formulation filled in the containers. In a two-shot-filling process (liquid filling followed by gaseous filling), it shall be ensured that 100 % check on weight is carried out.	Why only two shot filling process? Is it not required for single shot process?
74)	Page No 122, Part XI, Point No. 8.10	Manufacture Filled containers shall be quarantined for a suitable period established by the manufacturer to detect leaking containers prior to testing, labelling and packing.	This should not be made mandatory. There are other methods of checking the leakages.
75)	Page No 122, Part XI, Point No. 9.1	Documentation In addition to the routine good manufacturing practices documentation, manufacturing records shall show the following additional information:-	Apart from spray testing all other are required for other dosage forms too.
76)	Page No 122, Part XII	PART XII Specific Requirements for Manufacture of Active Pharmaceutical Ingredients Note:  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, the following specific requirements shall also be followed, namely:-	Some requirements given in Part 1 especially related Premises, storage areas, water, sampling of starting materials etc may not be fully applicable for APIs.   Since all the aspects of ICH Q7 are covered in this Part, this can be standalone document, separate from the requirements of drug products instead of addendum to Part 1.. This can be made as Part 2 with title of Good Manufacturing practices for Active Pharmaceutical Ingredients.
77)	Page No 157, Part XIII	PART XIII Requirements of Plant and Equipment	This section should be deleted. In the main part it is mentioned that appropriate equipment required for the manufacturing should be available, so there is no need to specify the equipment for different types of products.

- Above comments were submitted by me to CDSCO in 2018 when the GSR was published for comments.